Unregulated absorption of iron in the duodenum leads to iron overload.

Under normal circumstances iron is absorbed in the duodenum mostly in form of ferrous (Fe²⁺) iron (Fig. 3-1). The absorption of iron depends on the iron stored in the body, but normally enterocytes in the duodenum absorb only 10% of the total amount of iron entering the duodenum (i.e., 1–2 mg, from the 10–20 mg of iron ingested) daily in the typical American diet.

Figure 3-1 Iron absorption. The absorption of iron in the duodenum depends on the total iron stores of the body. Total iron body stores are reflected in the saturation of transferrin, the principal iron transport protein in the plasma. Transferrin binds to the immature precursors of normal enterocytes, which serve as iron sensors in the intestine. HFE gene product on these immature cells acts together with the transferrin receptor to differentiate into absorptively active enterocytes. Absorptively active enterocytes take up ferrous iron through the action of divalent metal transporter 1 (DMT-1). Absorbed iron is either stored in the cytoplasm as ferritin or transferred to the interstitial space by the basolateral protein called ferroportin. The action of DMT-1 and ferroportin in enterocytes and ferroportin in macrophages is regulated hepcidin, a liver-derived plasma protein. In hemochromatosis liver secretes less hepcidin than normal, and the HFE mutation affects its normal function.

Low iron stores increase iron absorption in mature enterocytes on the surface of the intestinal villi. These cells absorb iron through the action of divalent metal transporter 1 (DMT-1). Absorbed iron is in part stored in the enterocytes and in part transported into the interstitial fluid by a laterobasal protein called ferroportin. The activity of DMT-1 and ferroportin is normally suppressed by hepcidin, a regulatory protein circulating in the plasma. Hepcidin prevents abnormally high absorption of iron in the duodenum. It is synthesized by the liver in response to iron. Hepcidin also inhibits the release of iron from macrophages. Plasma hepcidin levels are low in persons with hereditary hemochromatosis.

The absorption of iron depends also on the transferrin iron sensors, which are expressed on the immature crypt cells. Note that these sensor cells do not participate in the absorption of iron in the intestine; instead they express receptors for transferrin and HFE gene product, which prime them to become absorptive enterocytes by activating the DMT-1/ferroportin system.

In hereditary hemochromatosis the mutation of HFE leads to an uncontrolled absorption of iron in the duodenum. The total iron stores, which are normally around 2.5 g for women and 3.5 g for men can be increased 10 to 20 times and even more. The saturation of the iron transport protein transferrin is also increased, and the excess iron is also excreted into the urine.

Iron is deposited in the form of ferritin, which aggregates into hemosiderin granules. Hemosiderin may be detected in many organs, where it causes tissue injury and functional disturbances. Excess iron also results in the formation of free radicals, which have the following adverse effects:

Iron overload causes pathologic changes in several vital organs.

Hemochromatosis may damage many organs, but most often the pathologic changes are seen in the liver (95%), skin (90%), pancreas (65%), joints (35%), and the heart (15%) (Fig. 3-2). Clinical symptoms usually manifest after age 40. Symptoms are 5 to 10 times less common in women, because normally women lose blood during menstruation and are thus less prone to accumulate iron. The symptoms occur later and are typically encountered several years after the onset of menopause.

Figure 3-2 Hemochromatosis. Iron accumulates in major organs causing tissue injury.

Liver. Iron accumulates in Kupffer cells, hepatocytes, and even in bile duct cells (Fig. 3-3). Deposits of iron pigment lead to fibrosis, gradually progressing to frank cirrhosis. Clinically these changes are associated with hepatomegaly, portal hypertension with splenomegaly, and esophageal varices. Other signs and symptoms of liver failure are also present in advanced cases. Liver cell carcinoma develops in 20% to 30% of patients with cirrhosis.

Figure 3-3 Hemochromatosis. Hemosiderin, demonstrated in this slide of a liver biopsy specimen as bluish pigment resulting from the Prussian blue reaction, is seen in the form of granules in liver cells and Kupffer cells.

Skin. Brown hyperpigmentation occurs in almost all patients who have cirrhosis. The hyperpigmentation, often described as “bronzing,” is due to accumulation of hemosiderin in dermal macrophages and the increased amount of melanin in the epidermis.

Endocrine glands. Accumulation of hemosiderin in the pancreas is associated with diabetes and related to injury of the islets of Langerhans. Diabetes mellitus develops more readily in persons who have a genetic predisposition and a family history of diabetes. Other endocrine organs may be affected as well, most notably the thyroid and the gonads. Testicular atrophy and consequences of reduced testosterone production (e.g., loss of libido, erectile dysfunction, gynecomastia) are common.

Joints. Deposits of hemosiderin cause joint injury typically associated with calcification of synovium and secondary changes in the adjacent bone. Many joints can be affected, but for unknown reasons the disease tends to begin with symptoms related to the second and third metacarpophalangeal joints.

Heart. Deposits of iron in the myocardium lead to cardiopathy with pump failure, dilatation of the heart, and conduction abnormalities.

Hemochromatosis is associated with diagnostic changes in iron metabolism.

Hemochromatosis is characterized by markedly increased body iron stores. The iron stores can be assessed with the use of several tests as follows:

These tests are usually performed as a battery to avoid false positive or negative results. For example, the serum ferritin level is markedly increased after extensive liver cell necrosis. Serum iron levels may be elevated in chronic alcoholics. Transferrin is a negative acute-phase protein, and its production is reduced in response to acute and many chronic diseases, as well as to malnutrition. Hence, its relatively high rate of saturation may be misleading sometimes.

Deposits of iron in the liver can be estimated subjectively in liver biopsy specimens stained with Prussian blue reacting with hemosiderin (see Fig. 3-3). Furthermore, the iron content of the liver biopsy specimen can be quantitated biochemically and expressed as iron in milligrams per gram of liver tissue. Liver containing increased amounts of iron appears denser than normal on CT or MRI examination. Genetic testing provides the final diagnosis. Genetic testing should also be offered to first-degree relatives. Treatment includes weekly phlebotomy to reduce the total iron content of the tissues.

Uric acid concentration in blood depends on the balance between production and excretion of uric acid.

Uric acid is the end product of the degradation of adenine and guanine. The immediate metabolic precursor of uric acid is xanthine (Fig. 3-4). Xanthine may be produced directly from guanine or from hypoxanthine through the action of xanthine oxidoreductase. This enzyme has a dual function, acting as oxidase and dehydrogenase. It also transforms xanthine into uric acid. Although the breakdown of nucleic acids occurs in all tissues, uric acid is produced only in organs, such as the liver and the intestines, that contain xanthine oxidoreductase.

Figure 3-4 Formation of uric acid. Uric acid is formed from xanthine, and is the end product of the degradation of adenine and guanine. Note that inosinic acid forms from phospho-α-D-ribosylpyrophosphate (PRPP) under negative feedback control (dotted line), and that the overproduction of xanthine from hypoxanthine and guanine is regulated by hypoxanthine-guanine phosophoribosyltransferase (HGPRT) in the so-called salvage pathway.

Overproduction of xanthine is prevented by hypoxanthine-guanine phosphoribosyl transferase (HGPRT), the primary enzyme involved in the so-called salvage pathway, which replenishes the inosinic and guanylic acid pools. Inosinic acid may be converted into adenylic acid and guanylic acid, both of which have a negative feedback effect on the formation of inosinic acid from phospho-α-D-ribosylpyrophosphate (PRPP).

The body contains approximately 1800 mg of uric acid, one third of which is turned over daily. Approximately two thirds of all uric acid is derived from the degradation of the purines, adenine and guanine (Fig. 3-5). The remaining third is derived from the diet. Two thirds of uric acid is eliminated from the blood in urine, and the remaining third through the intestines.

Figure 3-5 Metabolism of purines. Purines are derived from food, are newly synthesized, or formed from DNA. Purines are metabolized into uric acid, which is excreted in the kidneys or the intestines. Deposition of uric acid crystals in tissue leads to gout.

Ionized uric acid binds to sodium, and in blood it is predominantly found in the form of monosodium urate. Under physiologic conditions monosodium urate is saturated at a concentration of 6.8 mg/dL (415 μmol/L), and at higher concentrations one would expect it to precipitate and form crystals. This, however, does not occur, because the blood contains some stabilizing substances that prevent such crystallization. The solubility of monosodium urate decreases at low temperature, which accounts for the deposition of urate crystals in the joint tissue of the big toe during attacks of gouty arthritis.

Uric acid is filtered in the glomeruli, but almost all of it entering the proximal tubule is reabsorbed. Uric acid is then secreted back into the tubules and again reabsorbed to a large extent, so that only 10% of the uric acid is finally excreted into the urine. One third of the blood uric acid is excreted into the lumen of the intestine, where it undergoes uricolysis by the normal intestinal flora.

Hyperuricemia may develop due to overproduction or underexcretion of uric acid.

Hyperuricemia can result from overproduction or underexcretion of uric acid. Excessive dietary intake of purines can play a role under both conditions. Furthermore, in some patients both overproduction and underexcretion of uric acid occur. Alcohol, one of the most common triggers of gouty arthritis, can stimulate overproduction and prevent excretion.

Overproduction of uric acid is found in an isolated form in only 10% of all patients with gout. The defect can be primary, as in some inborn errors of metabolism, or secondary, when the excessive production of purines is related to increased cell lysis or turnover.

Overproducers of uric acid excrete uric acid in the urine in excess of 750 to 1000 mg/day, which may lead to the formation of uric acid stones in the urinary system. Overproduction of uric acid should be suspected if the attack of gout occurs at an early age, if there is a family history of early onset of gout, or if the uric acid renal stones are the first clinical sign of hyperuricemia.

Underexcretion of uric acid accounts for hyperuricemia in 90% of all patients with gout. These patients excrete less than 700 mg of uric acid per day. The causes include the following:

Deposits of uric acid crystals in the joints cause inflammation.

Patients who have hyperuricemia tend to form deposits of monosodium phosphate in the connective tissue capsule of joints. These aggregates, called microtophi, may then spontaneously release monosodium urate into the synovial fluid, or a larger bolus of it is released due to mechanical trauma. Crystals in the synovial fluid have an irritating effect on the synovium and also have a chemotactic effect on neutrophils, which enter the joint cavity, thus contributing to the inflammation. The crystals also become coated with complement and immunoglobulin from exudated plasma. Complement and immunoglobulin act as opsonins, thus enabling the neutrophils to phagocytize the crystals. Activated neutrophils also produce oxygen radicals, arachidonic acid derivatives, and cytokines, which stimulate inflammation, cause vasodilation, and increase vascular permeability. These events account for the redness of the joint and its swelling. Crystals ingested into the phagocytic vacuoles of neutrophils tend to pierce the lysosomes, thus allowing a discharge of lytic enzyme into the extracellular space. Once initiated, the inflammation is autocatalytic and self-sustained, lasting for several days until it slowly abates (Fig. 3-6).

Figure 3-6 Acute arthritis in gout. Crystals of monosodium urate initiate the inflammation and act as chemoattractants for neutrophils. Crystals are covered with immunoglobulin and complement C3, which serve as opsonins, facilitating the phagocytosis of crystals. Lytic enzymes released from phagocytic vacuoles contribute to inflammation.

Chronic deposits of uric acid crystals lead to the formation of tophi.

Microscopic aggregates of monosodium urate crystals tend to enlarge with time until they transform into nodular masses visible by the naked eye or in radiographs in the periarticular bone. These nodules are called tophi (from the Latin word tophus, meaning porous stone). Most often they are found around the joints and the subchondral bone or subcutaneous tissue (Fig. 3-7). Typical locations are the metatarsophalangeal joint of the big toe, Achilles and infrapatellar tendons, the elbow and fingers, or the pinna of the ear. Tophi may form also in internal organs, such as the kidneys, but less commonly than in subcutaneous sites and around joints.

Figure 3-7 Gout and hyperuricemia. The most common sites of monosodium urate crystal deposition.

The formation of tophi is directly related to the duration of gout and the severity of hyperuricemia. They almost never occur in asymptomatic hyperuricemia.

Tophi act as space-occupying lesions and may cause pain, deformities of joints, and chronic inflammation. Bulging tophi may ulcerate the skin, and those inside the bone may erode the bone and cause large defects.

Hyperuricemia may damage kidneys and cause nephrolithiasis.

Prolonged hyperuricemia may affect the function of renal tubules (urate nephropathy). Deposits of monosodium phosphates are found in the medulla, where they may cause tissue injury and predispose a person to secondary infection (pyelonephritis). Uric acid stones are formed in acid urine. The incidence of calcium phosphate stones is also increased.

Alcohol has direct effects on the brain.

Alcohol acts on brain cells as a toxin. It changes the fluidity of cell membranes, affecting the transmission of neural impulses, thus causing depression of neural activity. Alcohol has a sedative effect on most neural centers, but the suppression of some centers may lead to a loss of inhibition of others. This may induce a feeling of relaxation or good mood, as well as increased motor activity or uncontrolled emotions. The effects are dose-dependent and can be predicted roughly from the blood alcohol concentration (Fig. 3-8) as follows:

Figure 3-8 Acute alcohol intoxication. The blood concentration depends on the amount of alcohol ingested. The approximate blood alcohol levels for a 70-kg man are shown, using a 120-mL wine glass as a unit. The average alcohol content of wine is 11–13 mg/dL, beer 4–6 mg/dL, and whiskey or other hard liquors 40–45 mg/dL. The alcohol is cleared from the body at the same rate irrespective of the type of drink that was ingested.

Blood alcohol concentration can be reliably predicted from the breath test, which is routinely used by law enforcement to check for alcohol intoxication in drivers. Most of the states define legal intoxication with alcohol as a blood alcohol level of 100 mg/dL (22 mmol/L) in a person driving a motor vehicle.

Alcohol is metabolized in the liver.

Alcohol is absorbed in the stomach and small intestine, from which it is transported into the liver. In liver cells alcohol is metabolized through the action of alcohol dehydrogenase in the cytosol, P₄₅₀ cytochrome (CYP2E) in the smooth endoplasmic reticulum of the microsomal fraction, and catalase in peroxisomes (Fig. 3-9).

Figure 3-9 Three enzymes play a key function in the metabolism of alcohol in liver cells: alcohol dehydrogenase, CYP2E (cytochrome P₄₅₀ enzyme in the smooth endoplasmic reticulum of the microsomal fraction), and catalase in peroxisomes. Alcohol dehydrogenase is the most important liver enzyme involved in oxidation of alcohol, transforming it into acetaldehyde, which is then oxidized to acetylcoenzyme A (CoA). Nicotine adenine dinucleotide (NAD⁺) is reduced to NADH in this process, as well as during the action of CYP2E, a toxic metabolite, which is in turn oxidized to acetyl CoA by aldehyde dehydrogenase.

Alcohol dehydrogenase is the most important liver enzyme involved in the oxidation of alcohol. It oxidizes alcohol into acetaldehyde, a toxic metabolite, which is in turn oxidized to acetyl coenzyme A by aldehyde dehydrogenase. Nicotine adenine dinucleotide (NAD⁺) is the cofactor for both oxidation reactions and in this process is reduced to NADH. An increased ratio of NADH to NAD⁺ inhibits the NAD⁺-dependent oxidation of lactate to pyruvate, leading to lactic acidosis. A lack of pyruvate may cause hypoglycemia, which is further exacerbated by poor intake of nutrients in chronic alcoholics. Beta oxidation of fatty acid is reduced and triglyceride formation enhanced, leading to fatty change in liver cells (Fig. 3-10). Hence, alcohol metabolism in the liver ultimately results in the formation of toxic products and metabolic disturbances affecting the function of liver cells. If these changes persist, fatty liver may progress into alcoholic steatohepatitis and finally into cirrhosis.

Figure 3-10 Biopsy specimen demonstrating fatty liver caused by alcohol abuse.

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